Schizophrenia is a severe mental illness affecting about 1% of the population in which disruptions in the physical connections of neural circuitry are unclear. Our goal is to further understand the underlying changes to neural circuitry that occur in schizophrenia to provide a foundation that is fundamental for better treatment. The nucleus accumbens is a region of convergence for afferents of many brain areas disrupted in schizophrenia, and is the major site of input into the basal ganglia from the mesolimbic dopamine system, making it a key area of interest for schizophrenia; dopamine hyperfunction in the dorsal striatum is a hallmark characteristic of the disorder, and the role of dopamine as central in schizophrenia is one of the most accepted hypotheses of the illness. Although there is evidence for the role of the ventral striatum in schizophrenia, the anatomical pathology of the nucleus accumbens in schizophrenia has largely been overlooked. The proposed research will test the hypothesis that subjects with schizophrenia have increased dopaminergic inputs in the nucleus accumbens compared to normal control cases using postmortem human tissue. The density of tyrosine hydroxylase immunolabeling, the rate limiting synthesizing enzyme of dopamine, will be determined in control subjects compared to groups of off- and on-drug schizophrenia subjects using optical densitometry and western blot assays. The proposed research will also determine the ultrastructural abnormalities present in the nucleus accumbens neurocircuitry of subjects with schizophrenia using 3- dimensional stereological counting at the electron microscopic level. Lastly, chronically antipsychotic drug- treated rats will provide a context for the interpretation of results from the postmortem human studies. Results from the proposed research will provide insight into the abnormal circuitry that may be a core feature of schizophrenia, further elucidate mechanisms of the illness, and offer insight into therapeutics which are not fully understood.